Tsang K Y, Zhu M, Even J, Gulley J, Arlen P, Schlom J
Laboratory of Tumor Immunology and Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Cancer Res. 2001 Oct 15;61(20):7568-76.
Human dendritic cells (DCs) express MHC class I and II molecules and several T-cell costimulatory molecules that contribute to their efficiency as antigen-presenting cells (APCs). Whereas most human DC populations uniformly express some costimulatory molecules such as B7-2 (CD86), previous studies have shown a wide variation in the expression of B7-1 (CD80) among different human DC preparations. In the studies reported here, we demonstrate that replication-defective avipox vectors expressing B7-1 can be used to rapidly and efficiently infect human DCs and can enhance the efficacy of human DCs to activate specific human T-cell populations. This has been demonstrated both in systems using peptide as a source of signal 1 and in systems using recombinant avipox vector to deliver signal 1. The antigen used in these studies was the tumor-associated human carcinoembryonic antigen (CEA). An immunodominant 9-mer CTL epitope for CEA (designated CAP-1) has been previously characterized (K. Y. Tsang et al., J. Natl. Cancer Inst. (Bethesda), 87: 982-990, 1995). The source of signal 1 used in these studies was (a) the CAP-1 peptide; (b) recombinant avipox-CEA; or (c) the dual transgene recombinant avipox-CEA/B7-1. These studies demonstrate that CEA-specific T cells are more efficiently activated using as APCs peptide-pulsed DCs infected with avipox-B7-1, as compared with peptide-pulsed DCs infected with wild-type vector, or with uninfected peptide-pulsed DCs. Greater activation of CEA-specific T cells was also obtained using as APCs DCs that were infected with avipox-CEA/B7-1 as compared with the use of DCs infected with avipox-CEA. A CEA tetramer was also used to isolate high- and low-tetramer-binding CEA-specific T-cell populations. Although both high- and low-tetramer-binding T cells had the ability to lyse CEA peptide-pulsed targets, only the high-tetramer-binding T cells had the ability to lyse colon carcinoma cells expressing CEA, which suggests the existence of tetramer-binding populations with different T-cell receptor (TCR) affinities. The demonstrated safety of recombinant avipox vectors in humans and the previously demonstrated ability to administer them multiple times without host immune response limitations indicate that these vectors expressing B7-1 have a potential use in enhancing the efficacy of human DC immunotherapy protocols using either peptide or recombinant vector to deliver signal 1.
人树突状细胞（DCs）表达MHC I类和II类分子以及几种T细胞共刺激分子，这些分子有助于其作为抗原呈递细胞（APC）的效率。虽然大多数人DC群体均匀表达一些共刺激分子，如B7-2（CD86），但先前的研究表明，不同人DC制剂中B7-1（CD80）的表达存在很大差异。在本文报道的研究中，我们证明表达B7-1的复制缺陷型禽痘病毒载体可用于快速有效地感染人DCs，并可增强人DCs激活特定人T细胞群体的功效。这在使用肽作为信号1来源的系统以及使用重组禽痘病毒载体传递信号1的系统中均得到了证实。这些研究中使用的抗原是肿瘤相关的人癌胚抗原（CEA）。先前已鉴定出CEA的一个免疫显性9聚体CTL表位（命名为CAP-1）（K.Y. Tsang等人，《美国国家癌症研究所杂志》（贝塞斯达），87:982-990，1995）。这些研究中使用的信号1来源为：（a）CAP-1肽；（b）重组禽痘-CEA；或（c）双转基因重组禽痘-CEA/B7-1。这些研究表明，与感染野生型载体的肽脉冲DCs或未感染的肽脉冲DCs相比，使用感染禽痘-B7-1的肽脉冲DCs作为APC可更有效地激活CEA特异性T细胞。与使用感染禽痘-CEA的DCs相比，使用感染禽痘-CEA/B7-1的DCs作为APC也能获得对CEA特异性T细胞的更大激活。还使用CEA四聚体分离高结合和低结合四聚体的CEA特异性T细胞群体。虽然高结合和低结合四聚体的T细胞都有裂解CEA肽脉冲靶标的能力，但只有高结合四聚体的T细胞有裂解表达CEA的结肠癌细胞的能力，这表明存在具有不同T细胞受体（TCR）亲和力的四聚体结合群体。重组禽痘病毒载体在人体中已证明的安全性以及先前证明的多次给药而不受宿主免疫反应限制的能力表明，这些表达B7-1的载体在增强使用肽或重组载体传递信号1的人DC免疫治疗方案的功效方面具有潜在用途。
